We have during the past twenty years developed a comprehensive multidisciplinary research program using the equine infectious anemia virus (EIAV) system to examine the fundamental mechanisms by which lentiviruses persist despite robust host immune responses, the nature of protective and enhancing virus-specific immunity, and the evaluation of experimental immunization strategies as models for HIV-1/AIDSvaccine development. While Lentivirus envelope variation is well documented, the impact of this variation on vaccine efficacy remains largely speculative at this time. In the current application we propose to examine the hypothesis that the EIAV Env is the primary determinant of vaccine efficacy and that effective vaccines must elicit appropriate humoral and cellular immune responses to conerved immunorecessive Env determinants to provide enduring broadly protective immunity. Moreover, we suggest that both the nature of the Env immunogen and its method of presentation affect vaccine immune specificity and efficacy and that both parameters must be optimized. Thus, the following specific aims are proposed: (i) To define the humoral and cellular immune determinants of Env proteins of geographically diverse primary isolates and to assess the effects of defined sequence variation on immunogenic and antigenic properties; (ii) To examine directly the role of defined primary envelope variations on protection by experimental EIAV vaccines previously shown to be protective to homologous virus challenge; and (iii) To develop and evaluate novel immunization strategies using VEE and AAV viral vectors to elicit enduring broadly protective vaccine immunity to diverse EIAV challenge. It is anticipated that the results of the proposed studies will provide novel insights into the impact of defined natural Env variation on immune phenotypes, the relationship of challenge Env variation to vaccine efficacy, and the potential for viral vector vaccines to achieve protective immunity. Thus, the results of these EIAV studies should be complementary to ongoing vaccine studies in other animal lentivirus systems and relevant to the design and evaluation candidate human AIDS vaccines.